Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

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51 Citations (Scopus)

Abstract

RATIONALE:: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE:: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS:: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-Tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10 m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca influx and subsequent apoptosis. CONCLUSIONS:: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.

Original languageEnglish
Pages (from-to)771-780
Number of pages10
JournalCirculation research
Volume112
Issue number5
DOIs
Publication statusPublished - Mar 1 2013

Keywords

  • apoptosis
  • atherosclerosis
  • diabetes mellitus
  • endothelium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Nakatsuka, A., Wada, J., Iseda, I., Teshigawara, S., Higashio, K., Murakami, K., Kanzaki, M., Inoue, K., Terami, T., Katayama, A., Hida, K., Eguchi, J., Ogawa, D., Matsuki, Y., Hiramatsu, R., Yagita, H., Kakuta, S., Iwakura, Y., & Makino, H. (2013). Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex. Circulation research, 112(5), 771-780. https://doi.org/10.1161/CIRCRESAHA.111.300049